The major objectives of this proposal are to better understand the theoretical and practical aspects of the clinical pharmacology of opioid analgesics in human. Such knowledge will allow for the development of scientifically based guidelines for the use of these drugs in the management of acute and chronic pain. Our previous studies have demonstrated the necessity and utility of pharmacokinetic pharmacodynamic models in clinical analgesic studies. The major areas for study will be to measure the active metabolites of morphine, specifically morphine-6-glucuronide,- glucuronide, following oral, parenteral and intrathecal routes to assess its contribution to the analgesic and side effects of morphine. Using our pharmacokinetic-pharmacodynamic model, we will study the pharmacological and psychological factors that relate to patient controlled analgesiac (PCA) and repetitive oral dosing on a fixed or prn schedule. Similarly, we hope to quantitatively define the development of tolerance to the pharmacodynamic effects of opioids during repetitive losing for pain management. Opioid analgesics administered by novel routes offer special advantages to the cancer patient with pain. We plan to continue to study the pharmacokinetic aspects of sublingual, subcutaneous, and intrathecal administration and to use a sheep model to further assess the pharmacokinetics of cerebrospinal fluid drug distribution. We have developed a methodology to assess pain in children and we will study the sensitivity of this method to define the relative potency of analgesics in children. Comparative studies of heroin and hydromorphone have been designed to assess the relative merits of each of these drugs in acute and chronic cancer pain management. These studies will be performed in patients with acute and chronic pain of cancer who represent an appropriate experimental group for the study of pain in humans.